Nausea and vomiting can follow the administration of many drugs, particularly anticancer or chemotherapeutic agents. The symptoms also often accompany infectious and non-infectious gastrointestinal disorders.
The initial manifestations of the vomiting response often involves nausea, in which gastric tone is reduced, gastric peristalsis is reduced or absent and the tone of the duodenum and upper jejunum is increased, such that their contents reflux. Ultimately, the upper portion of the stomach relaxes while the pylorus constricts, and the coordinated contraction of the diaphragm and abdominal muscles leads to expulsion of gastric contents. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, New York, pp. 925-928 (1990).
Many workers have studied the effects of various drugs in alleviating the symptoms of emesis. In the Goodman and Gilman text, the authors mention metoclopramide (MTC), a benzamide, as a dopaminergic antagonist with important antiemetic uses. Benzodiazepines, another class of drugs, can enhance the effectiveness of antiemetic regimens and are thought to be beneficial in the prevention of anticipatory emesis. Also, dexamethasone (DEX) and other glucocorticoids are said to have antiemetic effects and may improve the efficacy of antiemetic regimens in some cancer patients. The authors name six phenothiazine compounds, one butyrophenone, two benzamides including metoclopramide and two cannabinoids as agents used in the treatment of nausea.
Goodman and Gilman describe metoclopramide as being well tolerated in high intravenous dosages and being widely used to control emesis during cancer chemotherapy, especially when highly emetogenic agents, such as cisplatin or cyclophosphamide, are used. Metoclopramide has been combined with diphenhydramine (DPH). Regimens that are reportedly effective in countering vomiting induced by cisplatin or cyclophosphamide include those that utilize the intravenous administration of metoclopramide and dexamethasone in combination with lorazepam plus benztropine or droperidol plus diphenhydramine.
In an article by Markman et al., in the New England Journal of Medicine, Vol. 311, pp. 549-552 (1984), the authors compare the antiemetic effects of dexamethasone with prochlorperazine. It is concluded that there is less nausea and vomiting with dexamethasone than with the prochlorperazine. The authors also refer to two studies comparing the efficacy of high-dose dexamethasone and high-dose metoclopramide. The dexamethasone was said to be more effective than metoclopramide in controlling chemotherapy-induced nausea and vomiting and was preferred by the patients treated.
In a review of metoclopramide, in Drugs 25:451-494 (1983), at page 453, the authors assert that controlled trials have shown oral metoclopramide (30-40 mg daily) alleviates the symptoms of gastro-oesophageal reflux relative to placebo and increases lower oesophageal sphincter pressure.
In a more recent publication, Roila, in Oncology 50:163-167 (1993), discusses the results of administering ondansetron plus dexamethasone, compared to the standard metoclopramide combination. In the paper, a composition comprising metoclopramide (3 mg/kg), dexamethasone (20 mg) and diphenhydramine (50 mg), administered intravenously, is compared with a composition of ondansetron (0.15 mg/kg) and dexamethasone (20 mg), administered intravenously. The results, summarized in the last line of the abstract at page 163, advises that ondansetron plus dexamethasone is a more effective and better tolerated antiemetic regimen compared with metoclopramide plus dexamethasone and diphenhydramine for the prevention of acute cisplatin-induced emesis.
In the patented literature, such as U.S. Pat. No. 5,039,528, metoclopramide is described as the agent of choice for suppressing emesis associated with cancer therapy. However, the patentee notes, this agent exhibits effective antiemetic activity only when used at high doses. In U.S. Pat. No. 5,482,716, the patentees indicate that studies show the antiemetic properties of carbazolone(1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)meth yl]-4H-carbazol-4-one) are enhanced by administering the compound in conjunction with dexamethasone, a systemic anti-inflammatory corticosteroid that is known to have antiemetic properties. In U.S. Pat. No. 5,310,561, in Example 6, ondansetron is used with metoclopramide, haloperidol or droperidol, and dexamethasone, among others.